Continuous Reactors
CSTR:
The continuous stirred-tank reactor (CSTR), also known as vat- or backmix reactor, is a common ideal reactor type in chemical engineering. A CSTR often refers to a model used to estimate the key unit operation variables when using a continuous agitated-tank reactor to reach a specified output. CSTR is extensively used in chemical industry.
PFR:
Plug flow reactors are tubular reactors or sometimes called as piston flow reactors. The key assumption is that as a plug flows through a PFR, the fluid is perfectly mixed in the radial direction but not in the axial direction (forwards or backwards). Each plug of differential volume is considered as a separate entity, effectively an infinitesimally small batch reactor, limiting to zero volume. As it flows down the tubular PFR, the residence time (t) of the plug is a function of its position in the reactor. Plug flow reactors have a high volumetric unit conversion, run for long periods of time without maintenance, and the heat transfer rate can be optimized by using more, thinner tubes or fewer, thicker tubes in parallel. Disadvantages of plug flow reactors are that temperatures are hard to control and can result in undesirable temperature gradients. PFR maintenance is also more expensive than CSTR maintenance. There are couple of examples where PFR has been extensively used: for fast and high temperature reactions like low density polyethylene reaction in large scale.
Reactive Separation:
Reactive Distillation:
Reactive Distillation (RD) is a combination of reaction and distillation in one unit operation owing to which it enjoys a number of specific advantages over conventional sequential approach of reaction followed by distillation or other separation techniques. Reactive distillation has been widely used for esterification reactions. This technique may be effectively used to improve the conversion of a reversible reaction by continuously removing one or more of the products.
Reactive distillation is a process where both the chemical reactions and the removal of the products happen simultaneously thus favoring the equilibrium limited reactions to a great extent. The reaction and the separation are normally carried out in a distillation column where three distinct zones exist viz. middle reaction zone, rectification zone at the top and stripping zone at the bottom of the column. The reaction can be accelerated using either homogeneous or heterogeneous catalysts in the reaction. A suitably designed reactive distillation column provides 100% conversion of reactant. The following advantages are obtained if the reaction is carried out in reactive distillation mode.                Improved efficiency due to better component separation        Lower costs—reduced equipment use, energy use and handling        Less waste and fewer byproducts        Improved product quality—reducing opportunity for degradation because of less heat        
The most spectacular benefits of RD are in the production of methyl acetate (U.S. Pat. No. 4,435,595, April 1982). The acid catalyzed reaction MeOH+AcOH⇄MeOAc+H2O which was traditionally carried out in one batch reactor and a train of nine distillation columns In RD implementation only one column is required and nearly 100% conversion of reactant is achieved.
However, the prior art does not report reactive distillation process to carry out the p-aminophenol and acetic acid reaction for the preparation of Paracetamol.
Membrane Reactor:
When a chemical reactor uses a membrane to aid or enhance the reactions by selectively separating products from the reaction mixtures or distributes products in different zones is called a membrane reactor. The main requirement of a membrane reactor is to have a semipermeable medium which selectively permits one of the products to pass through while retaining others. In particular, membrane bioreactors are applied extensively for the manufacture of biological products using enzyme reactions, and are common in the pharmaceutical/biomedical industry. They enhance the sustainability of a process by replacing more energy-intensive techniques such as distillation and evaporation. They are also operationally much simpler, and can be made to be highly selective to the specific desired process (EP 1 627 041 B1).
Pervaporation Unit:
Pervaporation: is a process in which a liquid stream containing two or more components is placed in contact with one side of a non-porous polymeric membrane while a vacuum or gas purge is applied to the other side. The components in the liquid stream sorb into the membrane, permeate through the membrane, and evaporate into the vapor phase. The vapor, referred to as “the permeate”, is then condensed. Due to different species in the feed mixture having different affinities for the membrane and different diffusion rates through the membrane, a component at low concentration in the feed can be highly enriched in the permeate. Further, the permeate composition may widely differ from that of the vapor evolved after a free vapor-liquid equilibrium process. Concentration factors range from the single digits to over 1,000, depending on the compounds, the membrane, and process conditions. In comparison with distillation, pervaporation is usually a more energy-saving process because the selectivity is largely improved because of the permselectivity of the membrane.
The applications of pervaporation processes for dehydration from alcoholic solutions and removal of organics from aqueous solutions have been carried out commercially for several years.
Chromatographic Reactor:
Chromatographic reactors integrate chemical reaction and chromatographic separation in one apparatus. This offers potential for process intensification, especially in the case of equilibrium reactions. Different types of discontinuous and continuous processes as well as modeling of chromatographic reactors are available. Synthesis and design of this processes is very much influenced and often restricted by the type of reaction and the operating window which is set by the individual operating conditions for chemical reaction, mass separation, and equipment design. Integrated chromatographic reactors should be considered if chromatography is the favored separation process for a conventional sequential process design. Synthesis of MTBE directly from methanol and tert-butyl alcohol is efficiently carried out in this type of reactor (Process for esterification in a chromatographic reactor, U.S. Pat. No. 6,586,609 July 2003).
U.S. Pat. No. 3,042,719, Jul. 3, 1962, discloses the purification of crude discolored N-acetyl-para-aminophenol (APAP) by acidifying an aqueous solution of the APAP with a mineral acid filtering the solution while hot. Filtrate cooled while adding an alkaline reducing sulfite e.g., sodium hydro sulfite
U.S. Pat. No. 3,113,150, Dec. 3, 1963, describes the preparation of pure APAP by neutralizing the wet APAP with ammonium hydroxide to remove excess acetic acid.
U.S. Pat. No. 3,748,358, Jul. 24, 1973, reveals the purification process of APAP by treating it with an acidic solution and then treating it in aqueous solution with carbon.
U.S. Pat. No. 3,781,354, Dec. 25, 1973, describes APAP purification by treating it in hot aqueous solution with ferric chloride and removing color by activated carbon.
U.S. Pat. No. 4,524,217, Jun. 18, 1985, describes a novel process for the preparation of APAP involving two steps. First step involves reacting 4-Hydroxyacetophenone with hydroxylamine salt and a base to obtain the ketoxime and subsequently Beckmann rearrangement of Ketoxime in the presence of catalyst to form APAP.
U.S. Pat. No. 4,264,526, Apr. 28, 1981, describes a process for the production of aminophenols and N-acetyl-p-aminophenol (APAP) comprising alkaline hydrolysis of halonitrobenzene to nitrophenol and from nitrophenols to aminophenols using a borate ion additive during hydrogenation to eliminate undesirable by-products and color formation.
U.S. Pat. Nos. 4,264,525, 4,565,890, 3,076,030, 3,341,587 and 5,155,269, describes acetylation of p-amino phenol was performed in the presence of acetic anhydride in aqueous solvent system. In U.S. Pat. No. 4,264,525 where batch process of acetylation is described. Quality of the APAP was good, giving only a slight pink caustic test and the product yield was 81.2%
CS Patent 223,945 (CI. C07C 91/44) Nov. 15, 1985 discloses a process wherein the acetylation of aminophenols with acetic anhydride in ethyl acetate or AcOH resulting in moderate yields of acetaminophen.
However, the drawback in most of the above mentioned process is the use of acetic anhydride as acetylating agent.
U.S. Pat. No. 4,565,890, January 21, describes a process wherein N-acetyl-p-aminophenol is prepared wherein p-aminophenol is acetylated in aqueous medium to produce a crude aqueous reaction mixture.
U.S. Pat. No. 4,670,589, Jun. 2, 1987 describes a process for the production of APAP by hydrogenation of p-nitrophenol to p-amino phenol (PAP), and concurrently acetylating the PAP with acetic anhydride.
U.S. Pat. No. 5,648,535, Jul. 15, 1997, describes a process for the production of N-acylaminophenols by the concurrent hydrogenation of a nitrophenol to an aminophenol and the acylation of the aminophenol with acyl anhydride on a continuous basis in a stirred tank reactor. The drawbacks in the above processes are the use of excess acetic anhydride as acetylating agent, difficulty in restricting to mono-acetylation of the amino group, longer reaction times, oligomerization of the hydroxyl aromatic amine, and color body formation.
U.S. Pat. No. 5,856,575, Jan. 5, 1989, describes a process for the manufacture of APAP which process comprises reacting an appropriate phenol and an amide in the presence of a heteropoly acid or its alkali metal salt catalyst.
U.S. Pat. No. 6,215,024, April 10, describes a novel step process for the production of amides from amines comprising reaction of amines with an acylating agent comprising of a carboxylic acid in a molar ratio of 1:3 to 1:10.
Indian patent Nos. IN2000MU00580, Jun. 22, 2000 describes a batch process for preparation of N-acetylated product of primary and secondary aromatic amines produced by N-acetylation of amines by heating with acetic acid, precipitating the product formed by adding water in conventional way, and recrystalising the N-acetylated product.
The aforementioned prior art processes have several limitations associated which is enumerated as follows:                Use of narcotic reagent acetic anhydride for acylation.        Batch process using acetic acid as acylating reagent leading to prolonged reaction time and lack of total completion of the reaction.        Prolonged reaction time for acetylation leading to colored product and formation of undesirable products as impurities.        Low yield <82% of the final product.        Cost ineffective processes.        Non ecofriendly processes.        
Hence, there was a long awaited need to develop a process obviating the above limitations. Applicant has now developed a continuous process for the preparation of N-acylated products of primary and secondary aromatic amines and O-acetylated product of hydroxy benzoic acid using acetic acid as an acetylating agent in improved yield and cost effective.